Vitamin A deficiency attenuates cardiac rupture in Stra6-deficient hearts following ischemic injury

Yannick Smolenski¹Natali Froese¹Paolo Galuppo¹Christopher Werlein¹Anna Gigina¹Steven R. Talbot¹Sergej Erschow¹Dirk Wedekind¹Robert Geffers²Norbert B. GHYSELINCK³Heike Bähre¹Jan Christopher Kamp¹Lavinia Neubert¹Melanie Ricke-Hoch¹Johann Bauersachs¹Christian Riehle^1*

• ¹Hannover Medical School, Hanover, Germany
• ²Helmholtz Center for Infection Research, Research Group Genome Analytics, Braunschweig, Germany
• ³IGBMC, Département de Génétique Fonctionnelle et Cancer, Centre National de la Recherche Scientifique (CNRS UMR7104), INSERM U1258, Université de Strasbourg, Illkirch, France

Background: Stimulated by retinoic acid gene 6 (STRA6) is a cell surface receptor that regulates cellular uptake of vitamin A metabolites and cardiac development. We hypothesized that Stra6 expression attenuates ischemic injury-induced heart failure following myocardial infarction (MI) by vitamin A-dependent mechanisms. Methods: MI was induced in mice with Stra6 germline deletion, vitamin A deficiency (VitAD) by combined lecithin-retinol acyltransferase (Lrat) germline deletion and feeding with a vitamin Adeficient diet. Contractile function was determined by transthoracic echocardiography, cardiac structure was assessed by histological analysis, and gene profiling was performed by RNA sequencing. Results: Stra6 deletion and VitAD did not impact contractile function and cardiac structure under basal conditions. Stra6 deficiency resulted in myocardial rupture, with the majority of mice dying by 4 days post-MI, which additional VitAD attenuated. Interestingly, contractile function, mRNA expression of heart failure markers, and cardiac structure were not different between groups 3 days post-MI. Gene profiling 3 days post-MI revealed decreased Wnt signaling in Stra6-deficient relative to wildtype hearts, which was reversed by VitAD. Conclusion: The present study identifies an unexpected role for VitAD, which preserves Wnt signaling and attenuates cardiac rupture in Stra6-deficient hearts following ischemic injury.